Full efficacy and safety analysis from GO29834 | Polatuzumab vedotin, obinutuzumab, and lenalidomide for R/R FL

In December 2019, at the 61^st American Society of Hematology (ASH) Meeting & Exposition, Catherine Diefenbach, Perlmutter Cancer Center at NYU Langone Health, New York, US, presented the primary analysis of the full efficacy and safety population of the phase Ib/II GO29834 trial (NCT02600897). GO29834 is an open-label multicenter study of polatuzumab vedotin (pola), obinutuzumab (G) and lenalidomide (len; pola-G-len) in patients with relapsed/refractory (R/R) follicular lymphoma (FL) who had received one, or more, prior anti-CD20-containing chemo-immunotherapy regimens. Catherine Diefenbach previously presented the results of the first pre-planned interim analysis of the trial during the American Society for Clinical Oncology (ASCO) meeting in June 2019. The results from the ASH presentation are summarized in this article, though data in this article may supersede that of the pre-published abstract. 

What is pola?

Pola is an antibody-drug conjugate targeting CD79b on B-cell receptors. Upon binding to CD79b on the tumor cell, pola is internalized by the cell where it directly delivers monomethyl auristatin E (MMAE), a microtubule disrupting agent, causing apoptosis.¹ Pola is already approved for the treatment of R/R diffuse large B-cell lymphoma (DLBCL), in combination with bendamustine and rituximab, by the United States (U.S.) Food & Drug Administration and European Medicines Agency (EMA).^2,3

Rationale for study

• ROMULUS: a phase Ib/II study (NCT01691898) of pola + G in patients with R/R DLBCL or FL. The results, presented by Tycel Phillips during the 2016 ASH meeting, showed pola + G had an acceptable safety profile and evidence of clinical activity in a population of patients who were heavily pre-treated or refractory to last prior regimen^4,5
• GALEN: a phase II study (NCT01582776) evaluating G + len in patients with R/R FL. At a median follow-up of 2.6 years, 79% of patients (68/86) achieved an overall response at end of induction (EOI), meeting the study’s primary endpoint⁶
• It was hypothesized therefore, that combining pola, G and len would form a potent anti-lymphoma combination and represent a new treatment option for patients with R/R FL¹

Study design¹

• GO29834 is a phase Ib/II, open label, single arm study with a dose escalation phase (3+3 design to determine the recommended phase II dose [RP2D] for pola + len), followed by an expansion phase
• The dose escalation phase found the RP2Ds to be: G: 1000 mg, pola: 1.4mg/kg and len: 20 mg
• In the expansion cohort, induction consisted of six 28-day cycles of:
  • G: 1000 mg intravenously (IV) on Days one, eight and 15 of Cycle one and Day one of Cycles 2–6
  • Pola: 1.4 mg/kg IV on Day one of each cycle
  • Len: 20 mg orally on Days 1–21 of each cycle
• Maintenance: given to responders (defined as patients achieving a complete response [CR], partial response [PR] or stable disease [SD]) for 24 months, as below:
  • G: 1000 mg IV on Day one every two months
  • Len: 10 mg daily on Days 1–21 for months 1–12
• The primary endpoint of the study was CR by EOI. This was assessed by an Independent Review Committee (IRC) based on the results of positron emission tomography-computed tomography (PET-CT) scans using the modified Lugano 2014 criteria. Progression-free survival (PFS) was investigator-assessed

Patient characteristics¹

Adult patients with Grade one, two or 3a R/R FL with ≥ 1 bi-dimensionally measurable lesion (≥ 1.5 cm in its longest dimension) with CD20⁺ cells and an Eastern Cooperative Oncology Group (ECOG) performance score between 0 and 2 were enrolled.

• Median age, years (range): 62 (32–87)
• FL International Prognostic Index (FLIPI) score ≥ 3 (high): 55%
• Median prior lines of therapy (range): 3 (1–7)
• Refractory to last prior therapy: 59%
• Relapse within 24 months of first-line treatment (POD24): 25%

Safety¹

• Median duration of follow-up for safety, months (range): 16.6 (2.1–39.5)
• The safety population (n= 56) consisted of 16 patients treated in the dose escalation portion of the study and 40 treated in the dose expansion phase
• Safety data are shown in Table 1, with Grade 3–4 adverse events (AEs) highlighted in Table 2
• The most common adverse events (AEs) of any grade occurring in ≥ 30% of patients were: infections and infestations (75%), neutropenia (64%), thrombocytopenia (52%), diarrhea (41%), anemia (39%), pyrexia (39%), infusion related reaction (34%) and peripheral neuropathy (30%)
• Grade 3–4 AEs occurring in ≥ 2 patients: 84%
• The most common Grade 3–4 AE was neutropenia (55%). Filgrastim (G-CSF) was not given prophylactically, but when given to treat neutropenia (in 55% of patients during induction and 36% during maintenance), and it did mitigate the severity
• AEs of special interest: four patients experienced tumor flare, with one patient developing myelodysplastic syndrome, and one developing a malignant lung neoplasm

Table 1. Safety data for the pola-G-len combination (N= 56)

AE; adverse event
*Grade five AE considered not related to study treatment. Patient experienced septic shock after progressive disease and new anti-lymphoma treatment

AE

N

%

Any grade AE

56

100

Grade five AE*

1

2

Grade 3–4 AE

47

84

Serious AE

32

57

AE leading to dose interruption

43

77

AE leading to dose reduction

19

34

AE leading to any drug discontinuation

17

30

Table 2. Grade 3–4 AEs occurring in > 10% of patients in the safety population (N= 56)

AE; adverse event

AE

N

%

Hematologic AEs

Neutropenia

31

55

Thrombocytopenia

15

27

Anemia

8

14

Febrile neutropenia

6

11

Non-hematologic AEs

Infections and infestations

11

20

Efficacy¹

Of the 56 patients that were evaluable for safety, six from the dose-escalation and 40 from the dose expansion cohorts were treated at the RP2D and were evaluable for efficacy (n= 46). Thirty-nine of the efficacy-evaluable population completed induction therapy.

A summary of efficacy analysis is shown in Table 3 (investigator assessed vs IRC assessed). The modified Lugano 2014 response criteria requires negative bone marrow (BM) biopsy, therefore patients with a CR by Lugano 2014 definition were downgraded to a PR category by the modified Lugano 2014 criteria if BM biopsy was missing. This occurred in six patients by investigator assessment and four by IRC, causing the difference in CR rates between Lugano 2014 and modified Lugano 2014 values (indicated in bold in Table 3).

PFS data were immature (not evaluable), however estimated 12-month PFS is 83.4% (95% CI, 70.85–95.96) at a median duration of follow-up of 15.1 months (range, 2.1–29.5).

Table 3. Efficacy analysis (N= 46) by Lugano 2014 and modified Lugano 2014 criteria as assessed by investigators, or IRC

CR; complete response, INV; investigator assessed, IRC; independent review committee assessed, NE; not evaluable, OR; objective response, PD; progressive disease, PR; partial response, SD; stable disease

 

Modified Lugano 2014

Lugano 2014

%

INV

IRC

INV

IRC

OR

83

76

83

76

CR

61

63

74

72

PR

22

13

9

4

SD

7

9

7

9

PD

7

2

7

2

Missing/NE

4

13

4

13

Subgroup analysis of high-risk patients (Table 4):

• FLIPI score: did not determine response to therapy with patients with high FLIPI scores having a comparable overall response rate (ORR) and CR rate to those with low FLIPI scores
• POD24: patients who were POD24 positive still achieved CRs (45%), though the rate was higher in patients who were not POD24 (80%)
• Refractory to last line of treatment: patients refractory to last line of treatment were also able to achieve a high CR rate (60%)
• Prior lines of therapy: patients receiving three or more prior therapies had comparable ORR and CR rates to those receiving 1–2 prior therapies

Table 4. Subgroup analysis in high-risk groups

CR; complete response, FLIPI; follicular lymphoma international prognostic index, ORR; overall response rate, POD24; progression of disease within 24 months

 

N

ORR, %

CR, %

FLIPI low (0–2) vs high (3–5)

20 vs 26

85 vs 70

75 vs 70

POD24 vs no POD24

11 vs 35

55 vs 83

45 vs 80

Refractory to last line of treatment vs not refractory

25 vs 21

68 vs 86

60 vs 86

Prior lines of treatment 1–2 vs ≥ 3

22 vs 24

77 vs 75

73 vs 71

Conclusion¹

In this first report of full efficacy data, the combination of pola-G-len was found to be well tolerated, with an acceptable safety profile consistent with each individual drug and led to high CR rates at EOI in a heavily pre-treated and refractory population. At 12 months, 83% of patients remained progression-free, with study investigators concluding that this novel combination warrants further investigation in patients with R/R FL.